Resistance To Thyroid Hormone Phenotype Research Articles

MON-472 A Case of Resistance to Thyroid Hormone with Concurrent Hashimoto’s Thyroiditis and Post-Surgical Hypothyroidism

Introduction: Resistance to thyroid hormone (RTH) is a rare defect that results in impaired sensitivity to thyroid hormone. While most commonly caused by mutations in the thyroid hormone receptor beta (THRβ) gene, in 15% of patients with the RTH phenotype, no mutation is identified.1 This entity is known as non-thyroid hormone receptor RTH (nonTR-RTH). Patients with RTH have an increased risk of autoimmune thyroid disease with a reported odds ratio of 2.36.2 Hashimoto’s thyroiditis or other etiologies of hypothyroidism add a layer of complexity to RTH as such individuals may require high doses of levothyroxine to overcome hormone resistance.Clinical Case: A 36-year-old male was referred for abnormal thyroid function tests. He denied symptoms of thyroid dysfunction. Physical examination was notable for a goiter. Weight was 83 kg. Initial labs revealed TSH 6.8 mcIU/mL (0.3-4.7 mcIU/mL), free T4 2.0 ng/dL (0.8-1.7 ng/dL), free T3 491 pg/dL (222-383 pg/dL), and thyroid peroxidase antibody >600 IU/mL (≤20 IU/mL). Additional work-up demonstrated elevated free T4 by equilibrium dialysis 2.5ng/dL (0.9-2.2 ng/dL) and elevated TSH with HAMA treatment 5.96 mIU/L (0.40-4.50 mIU/L), thereby ruling out familial dysalbuminemic hyperthyroxinemia and HAMA interference. Alpha-subunit of 0.30 ng/mL (<0.55 ng/mL) and normal pituitary MRI did not support a TSH-secreting adenoma. Quest Diagnostics RTH Gene Sequencing was negative for a mutation in the THRβ gene. The patient was subsequently diagnosed with nonTR-RTH. Thyroid ultrasound showed multiple thyroid nodules, including a 1.8 cm hypoechoic, complex nodule in the left inferior gland and a 1.7 cm isoechoic nodule in the right inferior gland. Fine needle aspiration of the left nodule was suspicious for papillary thyroid carcinoma and the right nodule showed lymphocytic thyroiditis. The patient underwent total thyroidectomy and pathology demonstrated a benign left nodule and an incidental 0.3 cm right papillary thyroid carcinoma. The patient started levothyroxine 150 mcg daily (1.8 mcg/kg) post-operatively with subsequent TSH of 18.1 mcIU/mL. His dose was increased to 200 mcg daily (2.4 mcg/kg) and TSH was still elevated at 11.7 mcIU/mL. His levothyroxine dose was subsequently increased to 250 mcg daily (3 mcg/kg) and TSH is outstanding.Conclusions: This case highlights the diagnostic challenge in nonTR-RTH. It also demonstrates the complex management of patients with RTH and concurrent hypothyroidism. Such patients need close monitoring and aggressive titration of levothyroxine to achieve desired hormone levels.1. Dumitrescu AM, Refetoff S. The syndromes of reduced sensitivity to thyroid hormone. Biochim Biophys Acta 2013;1830:3987-4003.2. Barkoff MS, Kocherginsky M, Anselmo J, Weiss RE, Refetoff S. Autoimmunity in patients with resistance to thyroid hormone. J Clin Endocrinol Metab 2010;95:3189-93.

Classification and proposed nomenclature for inherited defects of thyroid hormone action, cell transport, and metabolism.

Resistance to thyroid hormone (RTH) was first described in 1967 (1), and the first mutations in the THRB gene were identified in 1989 (2, 3), only 3 years after the cloning of the THR genes (4, 5). The cardinal features of this syndrome of reduced sensitivity to thyroid hormone are elevated serum levels of free thyroid hormone with nonsuppressed TSH, often with goiter and no clear symptoms and signs of thyrotoxicosis (6). In fact, signs of decreased and increased thyroid hormone action in different tissues may coexist. During the First International Workshop on Resistance to Thyroid Hormone in Cambridge, United Kingdom in 1993, a consensus statement was issued to establish a unified nomenclature of THRB gene mutations in RTH (7), as defined above. In the ensuing years more than 3000 cases have been identified, 80% of which harbored mutations in the THRB gene. More recently, two syndromes with reduced cellular access of the biologically active thyroid hormone, T3, were identified. These are caused by defects of thyroid hormone cell membrane transport (8, 9) and a defect reducing the intracellular metabolism generating T3 from T4 (10). To accommodate these new findings, it was proposed to broaden the definition of hormone resistance. Thus, the Fifth International Workshop on Resistance to Thyroid Hormone, which took place in Lyon, France, in 2005, saw the introduction of the term “reduced sensitivity to thyroid hormone (RSTH) to encompass all defects that can interfere with the biological activity of a chemically intact thyroid hormone secreted in normal or excessive amounts.” Following the 10th International Workshop on Resistance to Thyroid Hormone and Action that took place in Quebec City, Canada, in 2012, a number of investigators took on the task to develop a nomenclature for inherited forms of impaired sensitivity to thyroid hormone (Table 1). The term “impaired” was to substitute for “reduced” because nascent data indicate that syndromes of increased sensitivity may also exist. We are cognizant that no nomenclature can fit perfectly all aspects of the described syndromes because variability exists. Several aspects were taken into consideration: the already existing nomenclature, new findings, and anticipated putative discoveries. For example, in over 2000 publications “RTH” is used to define a phenotype of congenitally increased free T4 with nonsuppressed TSH, irrespective of the presence or absence of a THRB gene mutation (see non-TR-RTH). In view of the identification of THRA gene mutations that present a distinct phenotype (11, 12), we propose using the term “RTH α”, and in new publications to use “RTH β” when a THRB gene mutation is present in association with the RTH phenotype. This allows the naming of new gene defects in individuals with the RTH phenotype. The use of the abbreviation “THR” as a synonym for RTH is discouraged, not only because the hormone is not resistant, but also because this abbreviation is used to denote other circumstances. Indeed, a Medline search using THR yielded over 20 000 references, only a few related to resistance to thyroid hormone. Table 1. Inheritable Forms of Impaired Sensitivity to Thyroid Hormone

Estudio clínico y molecular de cinco familias con resistencia a la acción de las hormonas tiroideas

Background and objective Resistance to thyroid hormone (RTH) is a syndrome mostly caused by mutations in thyroid hormone receptor beta gen (THRB). We present five families with RTH phenotype. Patients and methods THRB gene sequencing. In vitro studies to evaluate the mutants response to thyroid hormones and their dominant negative effect. Mechanism of resistance in patients with RTH without THRB mutations quantifying expression of regulator of calcineurin 2 (ZAKI4) and Kruppel-like factor 9 (BTEB) genes in patients fibroblast cultures. Results THRB mutations were found in three cases: R243Q, R320C, R429Q. Mutants showed a decreased response to T3. R243Q and R320C had a strong dominant negative effect. One subject without THRB mutation showed changes in ZAKI4 and BTEB expression similar to R320C and the other showed expression levels higher than normal controls. Conclusions Three cases of RTH were caused by THRB heterozygous mutations but in two cases mutations were not found. THRB mutation carriers and one of the patients without mutations share a similar mechanism of resistance and in the other subject RTH is TRβ independent.

Resistance to Thyroid Hormone and Cardiovascular Risk

Resistance to thyroid hormone (RTH) is a dominantly inherited syndrome of impaired tissue responsiveness to thyroid hormones (TH) characterised by high circulating TH in the presence of unsuppressed thyroid-stimulating hormone (TSH). TH achieve their action on the heart chiefly via thyroid hormone receptor alpha 1 (TRa1), which is the TH receptor (TR) isoform predominantly expressed in such an organ. Data derived from animal models suggest that in RTH the overstimulation of the TRa1 pathway by the high TH levels could explain the cardiovascular abnormalities seen in these animals, although the discordant cardiac gene expression profile between wild-type (wt) and transgenic mice treated with triiodothyronine (T3) imply that the effects of RTH on the heart are complex and not completely explicable by the heightened T3/TRa1 signalling. To date, only a few studies have evaluated cardiovascular risk in RTH, with conflicting results, confirming the large variability of the RTH phenotype. In particular, some reports show that several cardiovascular parameters seem to move towards hyperthyroidism, while others show a pattern that resembles thyroid hormone deficiency. Finally, recent data suggest that in addition to reduced vascular compliance and echocardiographic abnormalities, RTH subjects may exhibit some features of metabolic syndrome, suggesting an overall increased cardiometabolic risk in this disorder.

Resistance to Thyroid Hormone and Cardiovascular Risk

Resistance to thyroid hormone (RTH) is a dominantly inherited syndrome of impaired tissue responsiveness to thyroid hormones (TH) characterized by high circulating TH in the presence of unsuppressed thyroid-stimulating hormone (TSH). TH achieve their action on the heart chiefly via thyroid hormone receptor alpha 1 (TR〈1), which is the TH receptor (TR) isoform predominantly expressed in such an organ. Data derived from animal models suggest that in RTH the overstimulation of the TR〈1 pathway by the high TH levels could explain the cardiovascular abnormalities seen in these animals, although the discordant cardiac gene expression profile between wild-type (wt) and transgenic mice treated with triiodothyronine (T3) imply that the effects of RTH on the heart are complex and not completely explicable by the heightened T3/TR〈1 signaling. To date, only a few studies have evaluated cardiovascular risk in RTH, with conflicting results, confirming the large variability of the RTH phenotype. In particular, some reports show that several cardiovascular parameters seem to move toward hyperthyroidism, while others show a pattern that resembles thyroid hormone deficiency. Finally, recent data suggest that in addition to reduced vascular compliance and echocardiographic abnormalities, RTH subjects may exhibit some features of metabolic syndrome, suggesting an overall increased cardiometabolic risk in this disorder.

E449X mutation in the thyroid hormone receptor β associated with autoimmune thyroid disease and severe neuropsychomotor involvement

To report the clinical and molecular aspects of a patient with a diagnosis of Resistance to Thyroid Hormone (RTH) harboring the E449X mutation associated with autoimmune thyroid disease and severe neuropsychomotor retardation. We present a case report including clinical and laboratory findings, and molecular analysis of a Brazilian patient with RTH. A 23-year old male presented hyperactivity disorder, attention deficit, delayed neuropsychomotor development, and goiter. Since the age of 1 year and 8 months, his mother had sought medical care for her son for the investigation of delayed neuropsychomotor development associated with irritability, aggressiveness, recurrent headache, profuse sudoresis, intermittent diarrhea, polyphagia, goiter, and low weight. Laboratory tests revealed normal TSH, increased T3, T4, antithyroglobulin and antimicrosomal antibody titers. Increasing doses of levothyroxine were prescribed, reaching 200 microg/day, without significant changes in his clinical-laboratory picture. Increasing doses of tiratricol were introduced, with a clear clinical improvement of aggressiveness, hyperactivity, tremor of the extremities, and greater weight gain. Molecular study revealed a nonsense mutation in exon 10, in which a substitution of a guanine to tyrosine in nucleotide 1345 (codon 449) generates the stop codon TAA, confirming the diagnosis of RTH. This patient has severe neuropsychomotor retardation not observed in a single previous report with the same mutation. This may reflect the lack of a genotype-phenotype correlation in affected cases with this syndrome, suggesting that genetic variability of factors other than beta receptor of thyroid hormone (TRbeta) might modulate the phenotype of RTH.

A Novel Mutation (E333D) in the Thyroid Hormone β Receptor Causing Resistance to Thyroid Hormone Syndrome

Resistance to thyroid hormone (RTH) is an inherited syndrome characterized by elevated serum thyroid hormones (TH), failure to suppress pituitary thyroid stimulating hormone (TSH) secretion, and variable peripheral tissue responsiveness to TH. The disorder is associated with diverse mutations in the thyroid hormone beta receptor (TRbeta). Here, we report a novel natural RTH mutation (E333D) located in the large carboxy-terminal ligand binding domain of TRbeta. The mutation was identified in a 22-year-old French woman coming to medical attention because of an increasing overweight. Biochemical tests showed elevated free thyroxine (T4: 20.8 pg/ml (normal, 8.5-18)) and triiodothyronine (T3: 5.7 pg/ml (normal, 1.4-4)) in the serum, together with an inappropriately nonsuppressed TSH level of 4.7 mU/ml (normal, 0.4-4). Her father and her brother's serum tests also showed biochemical abnormalities consistent with RTH. Direct sequencing of the TRbeta gene revealed a heterozygous transition 1284A>C in exon 9 resulting in substitution of glutamic acid 333 by aspartic acid residue (E333D). Further functional analyses of the novel TRbeta mutant were conducted. We found that the E333D mutation neither significantly affected the affinity of the receptor for T3 nor modified heterodimer formation with retinoid X receptor (RXR) when bound to DNA. However, in transient transfection assays, the E333D TRbeta mutant exhibited impaired transcriptional regulation on two distinct positively regulated thyroid response elements (F2- and DR4-TREs) as well as on the negatively regulated human TSHalpha promoter. Moreover, a dominant inhibition of the wild-type TRbeta counterpart transactivation function was observed on both a positive (F2-TRE) and a negative (TSHalpha) promoter. These results strongly suggest that the E333D TRbeta mutation is responsible for the RTH phenotype in the proposita's family.

Normal Cord Blood Thyroid-Stimulating Hormone in a Child with Resistance to Thyroid Hormone

An 8-year-old asymptomatic child was genetically diagnosed to have resistance to thyroid hormone (RTH) during a family screening. The disease-causing mutation is inherited from his father. Retrospective study showed the boy had a normal umbilical cord blood thyrotropin (TSH) level, suggesting that umbilical cord blood TSH may not reflect the fetal pituitary-thyroid axis abnormality and prenatal diagnosis and treatment should not be recommended in patients with mild RTH phenotype.

ADe NovoMutation in an Already Mutant Nucleotide of the Thyroid Hormone Receptor β Gene Perpetuates Resistance to Thyroid Hormone

Resistance to thyroid hormone (RTH) is a syndrome of reduced sensitivity to thyroid hormone, most commonly caused by mutations in the thyroid hormone receptor (TR) beta gene. Mutations are mostly located in the ligand-binding domain of the TRbeta, decreasing T(3) binding to the mutant TRbeta molecule, which in turn interferes with the function of the wild-type (WT) TR. A total of 122 different TRbeta gene mutations have been identified so far, with 46 occurring in more than one family. We now report a family with two novel TRbeta mutations occurring in the same nucleotide. The proposita had two children from each of her two marriages. One daughter and one son from each marriage had severe RTH with free T(4) and T(3) levels 3- to 4-fold the mean normal values and unsuppressed TSH, mental retardation, and deafness. The proposita had a missense mutation (GTG to GGG) in codon 458 of the TRbeta gene, resulting in the replacement of the normal valine with glycine (V458G). Although this mutation was transmitted to her affected son, the mutated codon in her affected daughter was GAG, encoding glutamic acid (V458E). Haplotype analysis showed that this de novo mutation occurred on the already mutant allele of the proposita. Cotransfection of each of these mutant TRbetas with the wild-type TRbeta showed a potent dominant negative effect. Large amounts of T(3) were required to dissociate homodimers of the mutant TRbeta bound to DNA. In addition, and in contrast to other mutant TRbetas with severe T(3)-binding defects, homodimer release failed to recruit the steroid receptor coactivator. No defects in heterodimerization with retinoid X receptor-alpha or association with a nuclear receptor corepressor, were identified. These in vitro data are in agreement with the in vivo phenotype of severe RTH. Unique and previously unreported in human inherited diseases is the occurrence of a de novo mutation at an already mutant nucleotide. Because the occurrence by chance is extremely unlikely, it is postulated that the presence of three guanines in the sequence created by the mutant nucleotide of the proposita results in a mutagenic site prone to de novo mutation.

Fetal loss associated with excess thyroid hormone exposure.

Maternal hypothyroidism and hyperthyroidism have deleterious effects on the outcome of pregnancy. While the effects of thyroid hormone (TH) deprivation on the fetus, independently from that on the mother, can be studied in infants with congenital hypothyroidism, this is not the case in those with fetal thyrotoxicosis. To study the effects of TH excess on fetuses carried by mothers with resistance to TH (RTH) who are euthyroid despite high TH levels but who may carry normal fetuses that are exposed to high maternal hormone levels. Retrospective study of 167 members of an Azorean family with RTH. Affected individuals had the RTH phenotype (high serum concentration of free thyroxine and triiodothyronine without suppressed thyrotropin) confirmed by genotyping to identify the Arg243-->Gln mutation in the TH receptor beta gene. Pregnancy outcome of affected mothers vs that of unaffected mothers carrying fetuses conceived by affected fathers, as well as that of unaffected first-degree relatives and outcomes from the general island population. Comparison of birth weights and blood concentrations of thyrotropin (TSH) obtained during routine neonatal screening of infants born to these 3 groups. Thirty-six couples with complete information belonged to 1 of 3 groups: affected mothers (n = 9), affected fathers (n = 9), and unaffected relatives (n = 18). Mean miscarriage rates were 22.9%, 2.0%, and 4.4%, respectively (chi2 = 8.66, P =.01). Affected mothers had an increased rate of miscarriage (z = 3.10, P =.002, by Wilcoxon rank-sum test). They had marginally higher than expected numbers of affected offspring, ie, 20 affected and 11 unaffected children (P =.07), while affected fathers had 15 affected and 12 unaffected children (P =.35). Unaffected infants born to affected mothers were significantly smaller than affected infants, having a mean SD score for gestational age of -1.79 (SD, 0.86) vs -0.06 (SD, 1.11) to -0.22 (SD, 0.70) for all other groups (P<.001). Only unaffected infants born to affected mothers had undetectable blood levels of TSH. There was a higher rate of miscarriage in mothers affected by RTH that may have involved predominantly unaffected fetuses. The lower birth weight and suppressed levels of TSH in unaffected infants born to affected mothers indicates that the high maternal TH levels produce fetal thyrotoxicosis. These data indicate a direct toxic effect of TH excess on the fetus.

Síndrome de resistência ao hormônio tireoidiano

Resistance to thyroid hormone (RTH) is a syndrome characterized by elevated serum thyroid hormone (TH) levels and elevated or inappropriately normal thyrotropin levels. In general, patients exhibit TH resistance in the pituitary and peripheral tissues. The phenotype of RTH is variable; the affected individuals are clinically euthyroid or even hypothyroid depending on the severity of the mutation, the variable hyposensitivity to TH among individuals as well as in different tissues. In almost all cases the genetic basis of RTH lies in mutation of the carboxyl-terminus of the ss-thyroid hormone receptor. RTH is a dominant disorder, except in one family; most individuals are heterozygous for the mutant allele. New standard techniques and genetically engineered mouse model systems have increased our understanding on TH receptor action, in particular, how mutant thyroid receptors from RTH patients can block wild-type thyroid receptor function (dominant negative activity), and how the mutant receptors can differently affect various tissues and individuals.

Diabetes mellitus in a girl with thyroid hormone resistance syndrome: a little recognized interaction between the two diseases

The syndrome of resistance to thyroid hormone (RTH) is characterized by elevated serum free thyroid hormones (FT4 and FT3) in the presence of unsuppressed TSH levels, reflecting resistance to the normal negative feedback mechanisms in the hypothalamus and pituitary. The degree of resistance within peripheral tissues determines whether thyrotoxic clinical features are associated with this condition. Classic features include attention deficit hyperactivity disorder, growth delay, tachycardia, and goiter. However, other features, such as frequent ear, nose and throat infections, hearing deficit, and decreased bone mass have recently been recognized. The phenotype of RTH is variable, with most patients presenting with mild to moderate symptoms. In this report we describe a girl with familiar RTH and diabetes mellitus. This is, to our knowledge, the first report regarding this association. Nearly one year after long-term triiodothyroacetic acid (Triac) therapy, we observed a reduction of thyroid hormone levels with an amelioration of insulin resistance. The possible interactions between these disorders are discussed.

Search for abnormalities of nuclear corepressors, coactivators, and a coregulator in families with resistance to thyroid hormone without mutations in thyroid hormone receptor beta or alpha genes.

The syndrome of resistance to thyroid hormone (RTH) is characterized by decreased tissue responsiveness to thyroid hormones. Inheritance is usually autosomal dominant due to mutations in the ligand-binding domain or adjacent hinge region of the thyroid hormone receptor beta (TRbeta) gene. Six of 65 families with the RTH phenotype studied in our laboratory had normal TRbeta1 and TRbeta2 gene sequences. Their clinical characteristics were not different from those of subjects with TRbeta gene mutations. Four of the 6 families were amenable to linkage analysis, and TRalpha involvement was excluded. Candidate genes were then evaluated for their possible involvement in the RTH phenotype in these 4 families: 2 coactivators [NCoA-1 (SRC-1) and NCoA-3 (AIB-1)], 2 corepressors (NCoR and SMRT), and a coregulator (RXRgamma). DNA was obtained from 8 affected subjects and 41 of 45 living first degree relatives. In 2 of the 4 families, the mode of inheritance could be determined by pedigree analysis and was found to be autosomal dominant. Linkage analyses were performed using polymorphic markers near or within the 5 candidate genes. When analyses were not informative or linkage could not be excluded, direct sequencing of the genes in question was performed. Involvement of NCoA-1 was excluded in all four families assuming autosomal dominant inheritance. Roles for NCoR, SMRT, and NCoA-3 were excluded in three and a role for RXRgamma was excluded in two of the four families. However, if the two families without proven dominant mode of inheritance were compound heterozygous, only the involvement of NCoA-1 could be excluded in both. Roles for NCoR, SMRT, and RXRgamma were excluded in one of these two families. Thus, NCoA-1 and RXRgamma genes were not found to be the cause of RTH in subjects without TR gene mutations even though the absence of NCoA-1 and RXRgamma is the cause of RTH in mice. Involvement of other candidate genes in the mediation of thyroid hormone action as well as intracellular hormone transport needs to be explored in these families with non-TRbeta, TRalpha RTH.

Resistance to thyroid hormone caused by two mutant thyroid hormone receptors beta, R243Q and R243W, with marked impairment of function that cannot be explained by altered in vitro 3,5,3'-triiodothyroinine binding affinity.

Resistance to thyroid hormone (RTH) is a syndrome of reduced responsiveness to thyroid hormone caused by mutations in the thyroid hormone receptor beta (TRbeta) gene. Mutant TRbetas exhibit variable degrees of impaired T3 binding resulting in reduced T3-mediated function. The dominant mode of inheritance is attributed to the ability of mutant TRbetas to interfere with the function of the wild-type (WT) TR, a phenomenon known as dominant negative effect (DNE). We recently identified two families with RTH having mutations in amino acid 243 (R243Q and R243W) in whom the mechanism of RTH appears to be distinct from that of other natural TRbeta mutations. These mutations, which are located in the hinge domain of the TRbeta, do not significantly alter the binding affinity for T3, measured in vitro. The present study was undertaken to characterize the properties of these mutant TRbetas to understand the molecular basis of the RTH phenotype. Two other mutant TRbeta producing RTH with mild (320H) and severe (345R) impairment of T3 binding were studied in parallel. The results demonstrate that TRbetas 243Q and 243W could be translocated into the nucleus where they exerted normal ligand-independent repression of positively regulated thyroid hormone response elements. Yet, the addition of 10 nmol/L T3 failed to normalize the transactivation (16-13% of WT) and revert the DNE exerted by the two TRbeta mutants. In contrast, at this T3 concentration, the transactivation function of 320H was significantly higher (50% of WT), and the DNE was completely abolished, in keeping with the mild clinical form of RTH. Formation of 243Q and 243W homodimers on thyroid hormone response elements could not be as readily prevented by T3 as those formed by the WT and 320H TRbetas. These results suggest that the substitution of R243 in TRbeta produces RTH by increasing the propensity for the formation of tightly bound homodimers or by reduction of the receptor affinity for T3 only after it binds to DNA.

A mouse model of resistance to thyroid hormone produced by somatic gene transfer of a mutant thyroid hormone receptor.

Resistance to thyroid hormone (RTH) is a dominantly inherited syndrome characterized by hyposensitivity to thyroid hormone caused by mutations in the thyroid hormone receptor-beta (TR beta) gene. Replication-defective recombinant adenoviruses were constructed that express the human wild-type (WT) TR beta, a human mutant TR beta identified in a family with RTH, and luciferase under the control of thyroid hormone (Luc). The efficient introduction and expression of these recombinant genes into adult mouse liver were confirmed by immunocytochemistry. Hypothyroid mice were infected with Luc alone and in combination with the WT TR beta or mutant TR beta. Half of the mice from each group were then treated with T3. Compared with mice infected with Luc alone, T3 treatment of mutant TR beta infected mice showed no changes in liver luciferase, weight, or 5'-deiodinase and spot 14 messenger RNA, and the decrease in the serum cholesterol concentration was blunted as in patients with RTH. The effects of T3 in mice infected with WT TR beta were comparable to those in mice infected with Luc alone. However, overexpression of the WT TR beta tended to further increase serum cholesterol in the hypothyroid state and decrease it in response to T3, suggesting that the unliganded TR has a constitutive effect in vivo and that higher TR levels can aggravate the manifestations of hypothyroidism and enhance the action of thyroid hormone. Transient somatic transfer of mutant TR genes provides a model for the study of RTH. It allows evaluation of the effect of genetic factors interacting with mutant TRs that modify the phenotype of RTH, without animal back-crossing.

A new point mutation (C446R) in the thyroid hormone receptor-beta gene of a family with resistance to thyroid hormone.

Resistance to thyroid hormone (RTH) is a condition of impaired end-organ responsiveness to thyroid hormone characterized by goiter and elevated thyroid hormone levels with an inappropriately normal TSH. RTH has been associated with mutations in the thyroid hormone receptor-beta (TR beta) gene. We report studies carried out in 21 members of a family (F119), 12 of whom exhibited the RTH phenotype. A point mutation was detected in the T3-binding domain of the TR beta gene. It resulted in replacement of the normal cysteine-446 with an arginine (C446R) that has not been previously reported. The clinical characteristics of this family are similar to those reported in other families with RTH, namely goiter, tachycardia, and learning disabilities. Thyroid function tests are also typical of other subjects with RTH. The mean values (+/- SD) in untreated affected subjects compared to those in unaffected family members were: free T4 index, 250 +/- 21 vs. 108 +/- 13; total T3, 4.3 +/- 0.4 vs. 2.4 +/- 0.4 nmol/L; and TSH, 4.5 +/- 1.1 vs. 2.4 +/- 1.1 mU/L. DNA samples from 18 family members were screened for the TR beta mutation, which results in the loss of a BsmI restriction site, and each of the 11 subjects with abnormal thyroid function tests were heterozygous for the mutant allele. The mutant TR beta expressed in Cos-I cells did not bind T3 (Ka of C446R/wild-type, < 0.05). T3 at a concentration up to 100 nmol/L failed to enhance the transactivation of a reporter gene, and the mutant receptor inhibited the T3-mediated transcriptional activation of the wild-type TR beta.